PCI is a procedure that opens narrowed arteries that supply heart muscle with blood. PCI with stent implantation is widely used to reduce the risk of mortality or myocardial infarction in patients with acute coronary syndromes and to reduce the burden of angina and improve the quality of life in patients with stable angina.1 However, thrombotic complications during PCI are a major concern, particularly if the procedure involves implantation of a stent, which can induce platelet adhesion, activation and thrombus formation on or near the stent.2 Thus, antiplatelet therapies are an important adjunct to PCI.3 1Mehta S R, et al., JAMA 2005; 293:2908-17; De Bruyne B, et al., N Engl J Med 2012; 367:991-1001 [Erratum, N Engl J Med 2012; 367:1768.]; Bhatt D L, JAMA 2005; 293:2935-7; Bavry A A, et al., J Am Coll Cardiol 2006; 48:1319-25; and Bhatt D L, et al., JAMA 2004; 292:2096-104.2Windecker S, et al., Circulation 2007; 116:1952-65; Maisel W H, N Engl J Med 2007; 356:981-4.3Grüntzig A R, et al., N Engl J Med 1979; 301:61-8.
Inhibition of platelet adenosine diphosphate (ADP) receptor P2Y12 through pharmacotherapy has been demonstrated to improve cardiovascular outcomes in patients undergoing PCI.4 Such antiplatelet therapies reduce the risk of ischemic events, particularly stent thrombosis.5 Yet, there are several limitations regarding the use of orally administered P2Y12-receptor inhibitors. For instance, there is a delayed onset of action when these drugs are administered, even when given with a loading dose,6 which is particularly problematic for patients who require urgent or periprocedural treatment. In addition, patients in the acute phase of cardiovascular illness may have conditions such as nausea, impaired absorption, or impaired perfusion that can limit drug bioavailability; in such patients the antiplatelet effect of oral antiplatelet agents such as clopidogrel may not be sufficient.7 Further, multiple studies have now demonstrated that the pharmacokinetic and pharmacodynamic effects of clopidogrel are highly variable8 and may be influenced by genetic polymorphisms,9 which translate into differential pharmacodynamic and therapeutic responses that lead to the notion of clopidogrel “non-responders.”10 Moreover, many physicians refrain from administering clopidogrel prior to angiographic definition of coronary anatomy, as this irreversible platelet inhibitor has been associated with an increased risk of perioperative bleeding if coronary artery bypass surgery is required rather than percutaneous revascularization. More potent oral ADP blockers have been tested and found to reduce ischemic outcomes even further, but with increased rates of bleeding.11 4Yusuf S, et al., N. Eng J Med 2001; 345:494-502; Mehta S R, et al., Lancet 2001; 358:527-33; Sabatine M S, et al., N Engl J Med 2005; 352:1179-89; and Steinhubl S R, et al., JAMA 2002; 288:2411-20 [Erratum, JAMA 2003; 289:987.].5Yousuf O, et al., Nat Rev Cardiol 2011; 8:547-59; Wiviott S D, et al., N Engl J Med 2007; 357:2001-15; Wallentin et al., N Engl J Med 2009; 361:1045-57; and Bhatt D L, N Engl J Med 2007; 357:2078-81.6Meadows T A, et al., Circ Res 2007; 100:1261-75.7Sou{hacek over (c)}ková L, et al., Eur J Clin Pharmacol 2013; 69:309-17 and Heestermans A A, et al., Thromb Res 2008; 122:7768Gurbel P A, et al., J Am Coll Cardiol 2005; 45:1392-6 and Collet J P, et al., Lancet 2009; 373:309-17.9Mega J L, et al., N Engl J Med 2009; 360:354-62.10Gurbel P A, et al., Nature Clin Pract Cardiovasc Med 2006; 3:387-95.11Wiviott S D, et al., N Engl J Med 2007; 357:2001-15; Bhatt D L, N Engl J Med 2007; 357:2078-81; Bhatt D L, N Engl J Med 2009; 361:940-2; Wallentin L, et al., N Engl J Med 2009; 361:1045-57; and Schömig A, et al., N Engl J Med 2009; 361:1108-11.
Thus, despite advances in adjunctive pharmacotherapy, the concern of ischemic events in a patient undergoing PCI has not been eliminated.12 Accordingly, there is a continuing need for a potent, fast-acting, reversible antiplatelet agent that effectively treats, reduces the incidence of, and/or prevents ischemic events without an excessive risk of bleeding. 12Stone G W, et al., N Engl J Med 2009; 360:1946-59 and Bavry A A, et al., Lancet 2008; 371:2134-33.